A pharmacologically quantified and reproducible animal model of barbiturate dependency, that was developed in this laboratory, will be used for a continued study of barbiturate dependency and withdrawal. Our initial aim is to apply this method in determining pharmacologic factors which contribute to the development of tolerance, alterations in pharmacokinetics and the production of dependency by (a) altering levels of chronic pentobarbital dosing (b) varying frequencies of adminstration and (c) changing durations of dosing. Utilizing the data obtained from these studies, it is now possible to rationally design a chronic dosing regimen for sedative hypnotics that will predict a minimal risk in producing tolerance and physical dependence in the patient. These same experimental variables will be considered in determining the tolerance, pharmacokinetic and withdrawal characteristics of other barbiturates and other CNS depressants, including ethanol and benzodiazepines. Using this dependency model, several possible drug therapies for withdrawal will be evaluated in whole animal and in an in vivo neuronal system. The effectiveness of benzodiazepines will be explored. Neurophysiologic alterations during barbiturate and ethanol withdrawal will be examined (1) by EEG from chronically implanted electrodes in various deep brain loci and also (2) by electrophysiologic measurements in segmental reflex pathways as a model. Our studies have uncovered certain synaptic vulnerabilities during barbiturate withdrawal which are considerably different from that produced during ethanol withdrawal are considerably different. Selective correction of neuronal disorders by potentially useful therapies will be tested. Studies of chronic barbiturate and ethanol effects and withdrawal on the normal sleep cycle will be continued. This offers a new dimension for studies of dependency-withdrawal effects on sleep, because, in this model, the dependency withdrawal states have been quantitatively defined.